During the current funding cycle, we made significant progress and made several key observations. First, we demonstrated that apo AIV is synthesized in the arcuate nucleus of the hypothalamus where adiposity signals act to influence energy homeostasis. Also, the administration of exogenous apo AIV either peripherally or centrally into the brain reduces food intake and body weight, and the administration of apo AIV antibodies centrally increases food intake. Second, obese rats maintained on a high fat saturated diet (HF-SAT, butter fat) have greatly reduced hypothalamic apo AIV gene and protein expression. Third. HF-SAT obese rats also have an attenuated intestinal and hypothalamic apo AIV gene and protein response to fasting and lipid feeding when compared to rats maintained on a low-fat (LF-SAT) diet or chow. Finally, we found that apo AIV knockout (KO) mice are more susceptible to high-fat (HF) diet-induced obesity. These observations imply that normal apo AIV activity is necessary to prevent obesity. Preliminary evidence from our Animal Core suggest that rats maintained on a diet matched in total fat but using olive oil (rich in oleic acid, a monounsaturated fat, abbreviated as HF-MONO) had less obesity than those on the HF-SAT diet. Furthermore, unlike the HF-SAT fed rats, the HF-MONO rats did not have reduced hypothalamic apo ATV gene expression. We hypothesize that apo AIV protects the animal against obesity caused by the chronic feeding of a HF-SAT diet and that the type of fatty acid in the diet regulates hypothalamic apo AIV gene and protein expression (saturated FA apo AIV expression while oleic acid is neutral). To test these hypotheses, we have proposed 4 specific aims. SPECIFIC AIM 1.2. (Project i, Specific Aim i) We will determine the role of intestinal apo AIV and hypothalamic apo AIV in diet-induced obesity caused by maintenance on a HF-SAT or a HF-MONO diet. SPECIFIC AIM 1.2. We will determine the interaction of apo AIV and CCKonfood intake and whether this interaction is influenced by maintenance on HF-SAT or HF-MONO. SPECIFIC AIM 1.3. We will test the hypothesis that gut peptides are differentially modified by dietary fats. SPECIFIC AIM 1.4. This specific aim utilizes the apo AIV knockout (KO) mouse as a tool to complement the other specific aims and to specifically address the question of whether apo AIV protects the animal against diet-induced obesity.